Tryptophan (Trp) is an essential amino acid in the human body. Part of the tryptophan obtained from the diet is used to synthesize protein, niacin and the neurotransmitter serotonin, and the rest is mainly metabolized by the kynurenine pathway (Leklem J. E., Am J Clin Nutr, 1971, 24 (6): 659-672), Indoleamine 2,3-dioxygenase (IDO) is a key enzyme involved in this metabolic pathway.
Indoleamine 2,3-dioxygenase is an intracellular heme-containing enzyme that was first discovered in the intestine of rabbits in 1967 (Yamaoto S. et al., J Biol Chem, 1967, 242(22): 5260-5266), and is the only rate-limiting enzyme outside the liver that can catalyze the oxidative pyrolysis of indole ring in tryptophan molecules and catabolize along the kynurenine pathway (MacKenzie, C. R. et al. Current Drug Metabolism, 2007, 8: 237-244).
IDO is widely distributed in extrahepatic tissues, especially in fibroblasts, epithelial cells, macrophages, dendritic cells (DCs), and microglia on the surface of mucosal tissue (such as placenta, lung and small intestine), and in thymus medulla and secondary lymphoid organ T cell region, gastrointestinal tract mucosa, epididymis, placenta, anterior chamber, etc., but is less expressed in the spleen, lymph nodes, and thymus cortex (Fusao Hirata et al., J Biol Chem, 1977 252(13): 4637-4642).
TDO is primarily expressed in the liver and controls the flow of tryptophan uptake from food into the serotonin and kynurenine pathway.
INF-specific inflammatory factors, such as IFN-γ, stimulate and induce the expression of IDO at the level of transcription. Other inflammatory factors, such as IFN-α, IFN-β and LPS, may also induce IDO expression, but the inductive effect is not as good as IFN-γ (King N. J. et al., The Int J Biochem Cell Biol, 2007 39(12): 2167-2172). At the same time, the expression of IDO is also regulated by immunologically active molecules such as prostaglandins, cell surface protein cytotoxic T lymphoce-associated antigen (CTLA24), CD40, and Toll-like receptors.
Recent studies have shown that IDO is involved in the regulation of T cell regulation. IDO can cleave T cell activation by degrading tryptophan since T cells are particularly sensitive to tryptophan depletion, and when tryptophan concentration is low, T cell proliferation will be stationary in G1 phase (Munn D. H. et al., J Exp Med, 1999, 189(9): 1363-1372). Based on this mechanism, IDO expressed in the placenta protects the fetus front maternal rejection (Munn D. H. et al., Science, 1998, 281(5380): 1191-1193); however, IDO expressed in tumors mediates immune escape of tumors (Friberg M. et al., Int J Cancer, 2002, 101(2): 151-155). IDOs on antigen-presenting cells such as macrophages and dendritic cells (DCs) can induce T cell immune tolerance to tumor antigens by inhibiting T cell proliferation (Terness P. et al., Blood, 2005, 105(6): 2480-2486).
IDO is closely related to nervous system diseases, and can affect the function of the brain through at least two mechanisms: 1) reducing the circulating tryptophan concentration by metabolizing tryptophan in the inflammatory reaction, thereby lowering the level of serotonin, and leading to depression 2) catalyzing the metabolism of tryptophan kynurenine pathway to accumulate kynurenine and neurotoxic quinolinic acid (Roy E. J. et al., Neurosci Lett, 2005, 387(2): 95-99).
IDO also involves the development of age-related nuclear cataract. IDO is the first enzyme in the biosynthesis of ultraviolet filters in the crystalline lens and is a rate-limiting enzyme. Ultraviolet filter compounds (kynurine and 3-hydroxykynurenine glucoside) from tryptophan degradation modify proteins presented in the human crystalline lens. The amount of these ultraviolet filter compounds increases with age (Takikawa et al. Adv. Exp. Med. Biol. 1999, 467, 241-245). It has also been reported that these ultraviolet filter compounds cause the crystalline lens to become opaque gradually, and thereby leads to the so-called age-related. nuclear cataract. IDO inhibitors block this natural process (Takikawa O. et al. Exp. Eye Res. 2001, 72, 271-277).
It is known in the conventional art that IDO inhibitors can be used to treat or prevent diseases having a pathological feature of IDO-mediated tryptophan metabolism pathways, including viral infections such as AIDS, Lyme disease and bacterial infections such as streptococcal infections, neurodegenerative disorders (e.g. Alzheimer's disease, Huntington's disease and Parkinson's disease), depression, cancer (including T-cell leukemia and colon cancer), eye diseases (e.g. cataracts and age-related yellowing) and autoimmune diseases (CN1795187A, CN101932325A, CN103054870A).
There are currently three IDO inhibitors in different clinical phases, including: 1) Epacadostat of Incyte, which is in Phase II clinical trials for the treatment of myelodysplastic syndromes, melanoma and female reproductive system cancer; 2) Indoximod of Newlink, which is in Phase II clinical trials for the treatment of breast cancer, prostate cancer, malignant brain tumors, pancreatic cancer and melanoma; 3) GDC-0919 of Roche, which is in Phase I clinical trials for the treatment of advanced solid tumors.
IDO is closely related to a variety of disease pathogenesis, and has been confirmed to be a target for major diseases such as cancer, Alzheimer's disease, depression, cataract (CN101932325B, CN102579452B). Therefore, IDO inhibitors have broad application prospects as drugs. However, no suitable IDO inhibitors have been marketed so far. IDO inhibitors currently in clinical research have the disadvantages of relatively high dose and relatively severe side effects. Therefore, it is of great theoretical significance and application value to find IDO inhibitors with higher IDO inhibitory activity and lower toxicity.